It remains unclear if the human coronary vasculature is inherently sensitive to changes in arterial PO2and PCO2or if coronary vascular responses are the result of concomitant increases in myocardial O2consumption/demand (MVO2). We hypothesized that the coronary vascular response to PO2and PCO2would be attenuated in healthy men when MVO2was attenuated with β1-adrenergic receptor blockade. Healthy men (n=11; age: 25 plus minus 1 years) received intravenous esmolol (β1-adrenergic receptor antagonist) or volume-matched saline in a double-blind, randomized, crossover study, and were exposed to poikilocapnic hypoxia, isocapnic hypoxia, and hypercapnic hypoxia. Measurements made at baseline and following 5-min of steady state at each gas manipulation included left anterior descending coronary blood velocity (LADV; Doppler echocardiography), heart rate and arterial blood pressure. LADVvalues at the end of each hypoxic condition were compared between esmolol and placebo. Rate pressure product (RPP) and left-ventricular mechanical energy (MELV) were calculated as indices of MVO2. All gas manipulations augmented RPP, MELV, and LADVbut only RPP and MELVwere attenuated (4-18%) following β1-adrenergic receptor blockade (Ptextless0.05). Despite attenuated RPP and MELV responses, β1-adrenergic receptor blockade did not attenuate the mean LADV vasodilatory response when compared to placebo during poikilocapnic hypoxia (29.4plus minus2.2 vs. 27.3plus minus1.6 cm/s) and isocapnic hypoxia (29.5plus minus1.5 vs. 30.3plus minus2.2 cm/s). Hypercapnic hypoxia elicited a feed-forward coronary dilation that was blocked by β1-adrenergic receptor blockade. These results indicate a direct influence of arterial PO2on coronary vascular regulation that is independent of MVO2.